{"gene":"MAPRE1","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2020,"finding":"MAPRE1 inhibits acetylation of α-tubulin and promotes dynamic assembly of microtubules, thereby enhancing invasion and migration capabilities of nasopharyngeal carcinoma cells.","method":"Proteomic comparison before/after circSETD3 knockdown/overexpression combined with functional invasion/migration assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, functional readout with proteomic support, but mechanistic detail on α-tubulin acetylation comes from abstract-level description without in vitro reconstitution","pmids":["33122825"],"is_preprint":false},{"year":2020,"finding":"MAPRE1 binds CDK2 and promotes hyperphosphorylation of CDK2 at Thr161, advancing cell cycle progression in hepatocellular carcinoma cells.","method":"Co-immunoprecipitation and phosphorylation assays in HCC cell lines with MAPRE1 knockdown/overexpression","journal":"Cell biology international","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP in cells with phosphorylation readout, single lab, two orthogonal methods (Co-IP + phospho-western)","pmids":["32770827"],"is_preprint":false},{"year":2022,"finding":"MAPRE1 forms a complex with CDK2 in chicken granulosa cells; miR-10a-5p suppresses CDK2 expression indirectly by repressing MAPRE1, thereby inhibiting cell cycle progression and progesterone synthesis.","method":"Co-immunoprecipitation, CCK-8, EdU assay, cell cycle analysis, qRT-PCR, western blot, ELISA","journal":"Theriogenology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP confirmed MAPRE1–CDK2 complex, multiple functional assays in single lab; chicken model may not fully recapitulate human biology","pmids":["36084389"],"is_preprint":false},{"year":2005,"finding":"In an MLL-EB1 (MAPRE1) chromosomal translocation, the resulting MLL-EB1 fusion protein localizes to the nucleus (rather than the normal microtubule-associated cytoplasmic localization of MAPRE1), as demonstrated by immunofluorescence staining.","method":"Immunofluorescence staining, cDNA panhandle PCR, RT-PCR, Southern blot","journal":"Genes, chromosomes & cancer","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, immunofluorescence for localization of fusion protein; confirms altered subcellular localization but no functional mechanism beyond localization change","pmids":["15751040"],"is_preprint":false},{"year":2025,"finding":"A macrocyclic FKBP12 ligand acting as a molecular glue recruits dimeric MAPRE1 to FKBP12, forming a 2:2:2 FKBP12:glue:MAPRE1 ternary complex; the X-ray crystal structure revealed interactions that occur exclusively in the ternary complex and confer significant cooperativity; ternary complex formation inhibits MAPRE1 interactions with its native intracellular partners.","method":"Protein array screen, TR-FRET, native MS, 2D protein NMR, X-ray crystallography, cellular NanoBiT assay","journal":"RSC chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — X-ray crystal structure with multiple orthogonal biophysical methods (NMR, native MS, TR-FRET) and cellular functional validation (NanoBiT) in single rigorous study","pmids":["40059881"],"is_preprint":false},{"year":2025,"finding":"CLASP2 directly interacts with MAPRE1 protein; the KHSRP/CLASP2/MAPRE1 axis promotes bladder cancer cell proliferation and cisplatin resistance, with MAPRE1 and CLASP2 co-localizing as shown by immunofluorescence.","method":"Co-immunoprecipitation, RNA immunoprecipitation, immunofluorescence, CCK-8, colony formation, flow cytometry, xenograft mouse model","journal":"The pharmacogenomics journal","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — Co-IP confirmed CLASP2–MAPRE1 protein interaction, single lab, but mechanistic detail between the interaction and functional output is limited in the abstract","pmids":["40382315"],"is_preprint":false}],"current_model":"MAPRE1 (EB1) is a microtubule plus-end tracking protein that promotes microtubule dynamic assembly, inhibits α-tubulin acetylation, and advances cell cycle progression by binding and activating CDK2 (via Thr161 hyperphosphorylation); it also interacts with CLASP2 at microtubule plus ends and can be incorporated into a druggable ternary complex with FKBP12 via molecular glue compounds that sterically block its native protein–protein interactions."},"narrative":{"mechanistic_narrative":"MAPRE1 (EB1) is a microtubule plus-end-associated protein that regulates microtubule dynamics and feeds into cell cycle progression. It inhibits α-tubulin acetylation and promotes dynamic microtubule assembly, an activity linked to enhanced invasion and migration of nasopharyngeal carcinoma cells [PMID:33122825]. MAPRE1 also binds CDK2 and promotes its hyperphosphorylation at Thr161, advancing cell cycle progression in hepatocellular carcinoma cells [PMID:32770827]; a MAPRE1–CDK2 complex was independently confirmed in granulosa cells, where MAPRE1 suppression reduces CDK2 expression and blocks cell cycle progression [PMID:36084389]. At microtubule plus ends MAPRE1 directly interacts and co-localizes with CLASP2, and this association supports proliferation and cisplatin resistance in bladder cancer cells [PMID:40382315]. The protein normally resides in a microtubule-associated cytoplasmic compartment; an MLL-EB1 chromosomal translocation produces a fusion protein that mislocalizes to the nucleus [PMID:15751040]. MAPRE1 functions as a dimer and can be sequestered into a 2:2:2 FKBP12:glue:MAPRE1 ternary complex by a macrocyclic molecular-glue ligand, which sterically blocks its native intracellular interactions [PMID:40059881].","teleology":[{"year":2005,"claim":"Establishing where MAPRE1 acts: the native protein occupies a microtubule-associated cytoplasmic compartment, and disrupting this localization through an MLL-EB1 fusion redirects it to the nucleus, linking the protein to oncogenic chromosomal rearrangement.","evidence":"Immunofluorescence and PCR/Southern characterization of an MLL-EB1 translocation","pmids":["15751040"],"confidence":"Medium","gaps":["No functional consequence of nuclear mislocalization defined","Wild-type MAPRE1 microtubule activity not assayed here"]},{"year":2020,"claim":"Defined a biochemical activity of MAPRE1 on the cytoskeleton: it inhibits α-tubulin acetylation and promotes dynamic microtubule assembly, connecting this to tumor cell invasion and migration.","evidence":"Proteomic comparison plus invasion/migration assays in nasopharyngeal carcinoma cells","pmids":["33122825"],"confidence":"Medium","gaps":["No in vitro reconstitution of the acetylation effect","Mechanism by which MAPRE1 affects acetylation undefined"]},{"year":2020,"claim":"Linked MAPRE1 to cell cycle control by showing it binds CDK2 and drives CDK2 Thr161 hyperphosphorylation to advance the cycle.","evidence":"Co-IP and phospho-western in HCC cell lines with knockdown/overexpression","pmids":["32770827"],"confidence":"Medium","gaps":["Whether MAPRE1 directly recruits the Thr161 kinase unknown","Single lab; no reciprocal validation of phosphorylation mechanism"]},{"year":2022,"claim":"Reinforced the MAPRE1–CDK2 axis in a second system, showing MAPRE1 supports CDK2 expression and cell cycle/progesterone output and is itself under miR-10a-5p control.","evidence":"Co-IP and multiple proliferation/cell cycle assays in chicken granulosa cells","pmids":["36084389"],"confidence":"Medium","gaps":["Chicken model may not recapitulate human biology","Direct versus indirect regulation of CDK2 levels not resolved"]},{"year":2025,"claim":"Identified a direct microtubule plus-end partner: CLASP2 binds and co-localizes with MAPRE1, and the axis promotes proliferation and chemoresistance.","evidence":"Co-IP, immunofluorescence, and proliferation/resistance assays plus xenograft in bladder cancer","pmids":["40382315"],"confidence":"Medium","gaps":["Mechanistic link between the interaction and functional output limited","Binding interface not mapped"]},{"year":2025,"claim":"Established MAPRE1 as a druggable dimeric target by showing a molecular-glue ligand sequesters it into a cooperative ternary complex with FKBP12 that blocks its native partner interactions.","evidence":"Protein array, TR-FRET, native MS, NMR, X-ray crystallography, and cellular NanoBiT","pmids":["40059881"],"confidence":"High","gaps":["Phenotypic consequence of blocking native interactions in disease cells not shown","Which native partners are most affected not defined"]},{"year":null,"claim":"How MAPRE1's microtubule plus-end tracking is mechanistically coupled to its CDK2-dependent cell cycle role remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of native MAPRE1 partner complexes (CDK2, CLASP2)","No reconstitution linking microtubule activity to cell cycle progression"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[3]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,2]}],"complexes":["FKBP12:glue:MAPRE1 ternary complex"],"partners":["CDK2","CLASP2","FKBP12"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15691","full_name":"Microtubule-associated protein RP/EB family member 1","aliases":["APC-binding protein EB1","End-binding protein 1","EB1"],"length_aa":268,"mass_kda":30.0,"function":"Plus-end tracking protein (+TIP) that binds to the plus-end of microtubules and regulates the dynamics of the microtubule cytoskeleton (PubMed:12388762, PubMed:16109370, PubMed:19632184, PubMed:21646404, PubMed:23001180, PubMed:28726242, PubMed:28814570, PubMed:34608293). Recruits other +TIP proteins to microtubules by binding to a conserved Ser-X-Leu-Pro (SXLP) motif in their polypeptide chains (PubMed:19632184, PubMed:36592928). Promotes cytoplasmic microtubule nucleation and elongation (PubMed:12388762, PubMed:16109370, PubMed:19632184, PubMed:21646404, PubMed:28726242, PubMed:28814570). Involved in mitotic spindle positioning by stabilizing microtubules and promoting dynamic connection between astral microtubules and the cortex during mitotic chromosome segregation (PubMed:12388762, PubMed:34608293). Assists chromosome alignment in metaphase by recruiting the SKA complex to the spindle and stabilizing its interactions with microtubule bundles (K-fibers) (PubMed:27225956, PubMed:36592928). Also acts as a regulator of minus-end microtubule organization: interacts with the complex formed by AKAP9 and PDE4DIP, leading to recruit CAMSAP2 to the Golgi apparatus, thereby tethering non-centrosomal minus-end microtubules to the Golgi, an important step for polarized cell movement (PubMed:28814570). Promotes elongation of CAMSAP2-decorated microtubule stretches on the minus-end of microtubules (PubMed:28814570). Acts as a regulator of autophagosome transport via interaction with CAMSAP2 (PubMed:28726242). Functions downstream of Rho GTPases and DIAPH1 in stable microtubule formation (By similarity). May play a role in cell migration (By similarity)","subcellular_location":"Cytoplasm, cytoskeleton; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Golgi apparatus; Cytoplasm, cytoskeleton, spindle; Cytoplasm, cytoskeleton, spindle pole","url":"https://www.uniprot.org/uniprotkb/Q15691/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MAPRE1","classification":"Not Classified","n_dependent_lines":355,"n_total_lines":1208,"dependency_fraction":0.29387417218543044},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000101367","cell_line_id":"CID000928","localizations":[{"compartment":"centrosome","grade":3},{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":1}],"interactors":[{"gene":"DCTN2","stoichiometry":10.0},{"gene":"RANBP2","stoichiometry":4.0},{"gene":"DYNC1LI1","stoichiometry":4.0},{"gene":"DYNC1H1","stoichiometry":4.0},{"gene":"DYNC1I2","stoichiometry":4.0},{"gene":"DYNLL1","stoichiometry":4.0},{"gene":"CBX1","stoichiometry":0.2},{"gene":"DYNLL2","stoichiometry":0.2},{"gene":"EDF1","stoichiometry":0.2},{"gene":"DKC1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000928","total_profiled":1310},"omim":[{"mim_id":"619358","title":"MICROTUBULE-ASSOCIATED SCAFFOLD PROTEIN 2; MTUS2","url":"https://www.omim.org/entry/619358"},{"mim_id":"615289","title":"MITOTIC SPINDLE-POSITIONING PROTEIN; MISP","url":"https://www.omim.org/entry/615289"},{"mim_id":"614570","title":"KINESIN FAMILY MEMBER 18B; KIF18B","url":"https://www.omim.org/entry/614570"},{"mim_id":"613199","title":"TAO KINASE 2; TAOK2","url":"https://www.omim.org/entry/613199"},{"mim_id":"610674","title":"SPERM FLAGELLAR PROTEIN 1; SPEF1","url":"https://www.omim.org/entry/610674"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Centrosome","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MAPRE1"},"hgnc":{"alias_symbol":["EB1"],"prev_symbol":[]},"alphafold":{"accession":"Q15691","domains":[{"cath_id":"1.10.418.10","chopping":"16-129","consensus_level":"high","plddt":96.7112,"start":16,"end":129},{"cath_id":"1.20.5.1430","chopping":"194-246","consensus_level":"high","plddt":89.5762,"start":194,"end":246}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15691","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15691-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15691-F1-predicted_aligned_error_v6.png","plddt_mean":80.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAPRE1","jax_strain_url":"https://www.jax.org/strain/search?query=MAPRE1"},"sequence":{"accession":"Q15691","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15691.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15691/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15691"}},"corpus_meta":[{"pmid":"21562367","id":"PMC_21562367","title":"Epigenetic regulation of microRNA-10b and targeting of oncogenic MAPRE1 in gastric cancer.","date":"2011","source":"Epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/21562367","citation_count":87,"is_preprint":false},{"pmid":"22277732","id":"PMC_22277732","title":"Increased plasma levels of the APC-interacting protein MAPRE1, LRG1, and IGFBP2 preceding a diagnosis of colorectal cancer in women.","date":"2012","source":"Cancer prevention research (Philadelphia, Pa.)","url":"https://pubmed.ncbi.nlm.nih.gov/22277732","citation_count":81,"is_preprint":false},{"pmid":"33122825","id":"PMC_33122825","title":"circSETD3 regulates MAPRE1 through miR-615-5p and miR-1538 sponges to promote migration and invasion in nasopharyngeal carcinoma.","date":"2020","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/33122825","citation_count":66,"is_preprint":false},{"pmid":"26342024","id":"PMC_26342024","title":"MAPRE1 as a plasma biomarker for early-stage colorectal cancer and adenomas.","date":"2015","source":"Cancer prevention research (Philadelphia, Pa.)","url":"https://pubmed.ncbi.nlm.nih.gov/26342024","citation_count":28,"is_preprint":false},{"pmid":"36084389","id":"PMC_36084389","title":"miR-10a-5p inhibits chicken granulosa cells proliferation and Progesterone(P4) synthesis by targeting MAPRE1 to suppress CDK2.","date":"2022","source":"Theriogenology","url":"https://pubmed.ncbi.nlm.nih.gov/36084389","citation_count":16,"is_preprint":false},{"pmid":"15751040","id":"PMC_15751040","title":"MLL is fused to EB1 (MAPRE1), which encodes a microtubule-associated protein, in a patient with acute lymphoblastic leukemia.","date":"2005","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/15751040","citation_count":14,"is_preprint":false},{"pmid":"32770827","id":"PMC_32770827","title":"MAPRE1 promotes cell cycle progression of hepatocellular carcinoma cells by interacting with CDK2.","date":"2020","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/32770827","citation_count":9,"is_preprint":false},{"pmid":"40059881","id":"PMC_40059881","title":"Identification and characterization of ternary complexes consisting of FKBP12, MAPRE1 and macrocyclic molecular glues.","date":"2025","source":"RSC chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/40059881","citation_count":4,"is_preprint":false},{"pmid":"35198024","id":"PMC_35198024","title":"MiR-526b-3p Inhibits the Resistance of Glioma Cells to Adriamycin by Targeting MAPRE1.","date":"2022","source":"Journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35198024","citation_count":4,"is_preprint":false},{"pmid":"40382315","id":"PMC_40382315","title":"KHSRP promotes the malignant behavior and cisplatin resistance of bladder cancer cells through the CLASP2/MAPRE1 axis.","date":"2025","source":"The pharmacogenomics journal","url":"https://pubmed.ncbi.nlm.nih.gov/40382315","citation_count":1,"is_preprint":false},{"pmid":"40243574","id":"PMC_40243574","title":"Experimental Conditions to Retrieve Intrinsic Cooperativity α Directly from Single Binding Assay Data Exemplified by the Ternary Complex Formation of FKBP12, MAPRE1 and Macrocyclic Molecular Glues.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40243574","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7994,"output_tokens":1478,"usd":0.023076,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8218,"output_tokens":2252,"usd":0.048695,"stage2_stop_reason":"end_turn"},"total_usd":0.071771,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"MAPRE1 inhibits acetylation of α-tubulin and promotes dynamic assembly of microtubules, thereby enhancing invasion and migration capabilities of nasopharyngeal carcinoma cells.\",\n      \"method\": \"Proteomic comparison before/after circSETD3 knockdown/overexpression combined with functional invasion/migration assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, functional readout with proteomic support, but mechanistic detail on α-tubulin acetylation comes from abstract-level description without in vitro reconstitution\",\n      \"pmids\": [\"33122825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MAPRE1 binds CDK2 and promotes hyperphosphorylation of CDK2 at Thr161, advancing cell cycle progression in hepatocellular carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation and phosphorylation assays in HCC cell lines with MAPRE1 knockdown/overexpression\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP in cells with phosphorylation readout, single lab, two orthogonal methods (Co-IP + phospho-western)\",\n      \"pmids\": [\"32770827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MAPRE1 forms a complex with CDK2 in chicken granulosa cells; miR-10a-5p suppresses CDK2 expression indirectly by repressing MAPRE1, thereby inhibiting cell cycle progression and progesterone synthesis.\",\n      \"method\": \"Co-immunoprecipitation, CCK-8, EdU assay, cell cycle analysis, qRT-PCR, western blot, ELISA\",\n      \"journal\": \"Theriogenology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP confirmed MAPRE1–CDK2 complex, multiple functional assays in single lab; chicken model may not fully recapitulate human biology\",\n      \"pmids\": [\"36084389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In an MLL-EB1 (MAPRE1) chromosomal translocation, the resulting MLL-EB1 fusion protein localizes to the nucleus (rather than the normal microtubule-associated cytoplasmic localization of MAPRE1), as demonstrated by immunofluorescence staining.\",\n      \"method\": \"Immunofluorescence staining, cDNA panhandle PCR, RT-PCR, Southern blot\",\n      \"journal\": \"Genes, chromosomes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, immunofluorescence for localization of fusion protein; confirms altered subcellular localization but no functional mechanism beyond localization change\",\n      \"pmids\": [\"15751040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A macrocyclic FKBP12 ligand acting as a molecular glue recruits dimeric MAPRE1 to FKBP12, forming a 2:2:2 FKBP12:glue:MAPRE1 ternary complex; the X-ray crystal structure revealed interactions that occur exclusively in the ternary complex and confer significant cooperativity; ternary complex formation inhibits MAPRE1 interactions with its native intracellular partners.\",\n      \"method\": \"Protein array screen, TR-FRET, native MS, 2D protein NMR, X-ray crystallography, cellular NanoBiT assay\",\n      \"journal\": \"RSC chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — X-ray crystal structure with multiple orthogonal biophysical methods (NMR, native MS, TR-FRET) and cellular functional validation (NanoBiT) in single rigorous study\",\n      \"pmids\": [\"40059881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CLASP2 directly interacts with MAPRE1 protein; the KHSRP/CLASP2/MAPRE1 axis promotes bladder cancer cell proliferation and cisplatin resistance, with MAPRE1 and CLASP2 co-localizing as shown by immunofluorescence.\",\n      \"method\": \"Co-immunoprecipitation, RNA immunoprecipitation, immunofluorescence, CCK-8, colony formation, flow cytometry, xenograft mouse model\",\n      \"journal\": \"The pharmacogenomics journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP confirmed CLASP2–MAPRE1 protein interaction, single lab, but mechanistic detail between the interaction and functional output is limited in the abstract\",\n      \"pmids\": [\"40382315\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAPRE1 (EB1) is a microtubule plus-end tracking protein that promotes microtubule dynamic assembly, inhibits α-tubulin acetylation, and advances cell cycle progression by binding and activating CDK2 (via Thr161 hyperphosphorylation); it also interacts with CLASP2 at microtubule plus ends and can be incorporated into a druggable ternary complex with FKBP12 via molecular glue compounds that sterically block its native protein–protein interactions.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MAPRE1 (EB1) is a microtubule plus-end-associated protein that regulates microtubule dynamics and feeds into cell cycle progression. It inhibits α-tubulin acetylation and promotes dynamic microtubule assembly, an activity linked to enhanced invasion and migration of nasopharyngeal carcinoma cells [#0]. MAPRE1 also binds CDK2 and promotes its hyperphosphorylation at Thr161, advancing cell cycle progression in hepatocellular carcinoma cells [#1]; a MAPRE1–CDK2 complex was independently confirmed in granulosa cells, where MAPRE1 suppression reduces CDK2 expression and blocks cell cycle progression [#2]. At microtubule plus ends MAPRE1 directly interacts and co-localizes with CLASP2, and this association supports proliferation and cisplatin resistance in bladder cancer cells [#5]. The protein normally resides in a microtubule-associated cytoplasmic compartment; an MLL-EB1 chromosomal translocation produces a fusion protein that mislocalizes to the nucleus [#3]. MAPRE1 functions as a dimer and can be sequestered into a 2:2:2 FKBP12:glue:MAPRE1 ternary complex by a macrocyclic molecular-glue ligand, which sterically blocks its native intracellular interactions [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing where MAPRE1 acts: the native protein occupies a microtubule-associated cytoplasmic compartment, and disrupting this localization through an MLL-EB1 fusion redirects it to the nucleus, linking the protein to oncogenic chromosomal rearrangement.\",\n      \"evidence\": \"Immunofluorescence and PCR/Southern characterization of an MLL-EB1 translocation\",\n      \"pmids\": [\"15751040\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional consequence of nuclear mislocalization defined\", \"Wild-type MAPRE1 microtubule activity not assayed here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a biochemical activity of MAPRE1 on the cytoskeleton: it inhibits α-tubulin acetylation and promotes dynamic microtubule assembly, connecting this to tumor cell invasion and migration.\",\n      \"evidence\": \"Proteomic comparison plus invasion/migration assays in nasopharyngeal carcinoma cells\",\n      \"pmids\": [\"33122825\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution of the acetylation effect\", \"Mechanism by which MAPRE1 affects acetylation undefined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked MAPRE1 to cell cycle control by showing it binds CDK2 and drives CDK2 Thr161 hyperphosphorylation to advance the cycle.\",\n      \"evidence\": \"Co-IP and phospho-western in HCC cell lines with knockdown/overexpression\",\n      \"pmids\": [\"32770827\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MAPRE1 directly recruits the Thr161 kinase unknown\", \"Single lab; no reciprocal validation of phosphorylation mechanism\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Reinforced the MAPRE1–CDK2 axis in a second system, showing MAPRE1 supports CDK2 expression and cell cycle/progesterone output and is itself under miR-10a-5p control.\",\n      \"evidence\": \"Co-IP and multiple proliferation/cell cycle assays in chicken granulosa cells\",\n      \"pmids\": [\"36084389\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Chicken model may not recapitulate human biology\", \"Direct versus indirect regulation of CDK2 levels not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a direct microtubule plus-end partner: CLASP2 binds and co-localizes with MAPRE1, and the axis promotes proliferation and chemoresistance.\",\n      \"evidence\": \"Co-IP, immunofluorescence, and proliferation/resistance assays plus xenograft in bladder cancer\",\n      \"pmids\": [\"40382315\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between the interaction and functional output limited\", \"Binding interface not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established MAPRE1 as a druggable dimeric target by showing a molecular-glue ligand sequesters it into a cooperative ternary complex with FKBP12 that blocks its native partner interactions.\",\n      \"evidence\": \"Protein array, TR-FRET, native MS, NMR, X-ray crystallography, and cellular NanoBiT\",\n      \"pmids\": [\"40059881\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phenotypic consequence of blocking native interactions in disease cells not shown\", \"Which native partners are most affected not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MAPRE1's microtubule plus-end tracking is mechanistically coupled to its CDK2-dependent cell cycle role remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of native MAPRE1 partner complexes (CDK2, CLASP2)\", \"No reconstitution linking microtubule activity to cell cycle progression\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [\"FKBP12:glue:MAPRE1 ternary complex\"],\n    \"partners\": [\"CDK2\", \"CLASP2\", \"FKBP12\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}